title: Tripeptidyl peptidase II regulates sperm function by modulating intracellular Ca(2+) stores via the ryanodine receptor.
abstract: Recent studies have identified Ca(2+) stores in sperm cells; however, it is not clear whether these Ca(2+) stores are functional and how they are mobilized. Here, in vitro and in vivo, we determined that tripeptidyl peptidase II antagonists strongly activated the cAMP/PKA signaling pathway that drives sperm capacitation-associated protein tyrosine phosphorylation. We demonstrated that in the absence of Ca(2+), TPIII antagonists elevated the intracellular Ca(2+) levels in sperm, resulting in a marked improvement in sperm movement, capacitation, acrosome reaction, and the in vitro fertilizing ability. This antagonist-induced release of intracellular Ca(2+) could be blocked by the inhibitors of ryanodine receptors (RyRs) which are the main intracellular Ca(2+) channels responsible for releasing stored Ca(2+). Consistent with these results, indirect immunofluorescence assay using anti-RyR antibodies further validated the presence of RyR3 in the acrosomal region of mature sperm. Thus, TPPII can regulate sperm maturation by modulating intracellular Ca(2+) stores via the type 3 RyR.
authors.affiliation: Shanghai Key Laboratory for Molecular Andrology, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Ru
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.forename: Shoulin
authors.initials: S
authors.lastname: Wang
authors.forename: Zuomin
authors.initials: Z
authors.lastname: Zhou
authors.forename: Yonglian
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D020101:Acrosome Reaction / Q000502:physiology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013075:Sperm Capacitation / Q000502:physiology; D013094:Spermatozoa / Q000166:cytology / Q000502:physiology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D007211:Indoles; D009125:Muscle Relaxants, Central; D019837:Ryanodine Receptor Calcium Release Channel; C098807:butabindide; C055604:alanyl-alanyl-phenylalanine chloromethyl ketone; D012433:Ryanodine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D003620:Dantrolene; D002118:Calcium